1. Field of the Invention
The present invention relates to a method and apparatus for the production of surface modified aerosol particles suitable for, for instance, therapeutic, cosmetic or diagnostic use. The method can be used for batch or continuous production. The invention also includes particles made according to the invention and powders and dispersions containing said particles.
2. Description of Related Art
Surface modification of particles is important in a number of fields related to, for instance, drug delivery and medical diagnostics and the synthesis of various multicomponent materials. The production of particles with well-defined chemical and physical properties (e.g. drug particle size, structure, crystallinity) is of interest in pharmaceutical applications, since the physical properties of the particles affect the dissolution and absorption rate, and bioavailability of the drug. Control of particle surface properties for stability and storage and for varying the dissolution rate in the body for, for instance, sustained release is also desirable. Moreover, in the field of drug delivery and medical diagnostics, due to the increasing use of pulmonary delivery of medicaments and diagnostic agents, dry powders having high flowability and dispersability are needed for repeatable dosing and efficient delivery to the lung. Inhalation has become the primary route of administration in the treatment of, for instance, asthma and COPD and is becoming ever more important for systemic delivery for diseases such as diabetes. This is because, besides providing direct access to the lungs, medication delivered through the respiratory tract provides rapid and predictable onset of action and requires lower dosages compared to the oral route.
The coating of nano and microparticles with hard crystalline material can be used improve the stability of the particles. Besides improved stability the coating is often used to modify the particle size and material surface properties. The surface properties (e.g. morphology, surface charge) of the particles affect the adhesion and detachment forces, which are important factors especially for inhalation applications. Adhesion forces (e.g. Van der Waals, capillary and electrical forces) significantly influence powder flowability (and thus dose repeatability) and aerosolisation of the powders and drug and carrier particle deagglomeration during delivery. In addition, coating can enable the controlled release of the active pharmaceutical agents that provides a way to avoid drug toxicity while delivering an optimum dose.
Numerous methods have been proposed to control the size, composition, morphology and crystalline structure and composition of inhalation powders using, for instance, precipitation or crystallization followed by drying and milling, supercritical fluid methods and spray drying. Conventional methods for the coating of pharmaceutical particles include chemical (e.g. co-precipitation of polymeric matrices), physicochemical (e.g. emulsion techniques) and mechanical techniques (e.g. fluidised bed coating, spray drying). Controlled coating on the inorganic core particles has been achieved with laser ablation techniques as well as with chemical vapor deposition (CVD) techniques. Recently, pharmaceutical powders were coated by physical vapor deposition (PVD) in a fluidized bed reactor. In solution, functional coatings for latexes can be, for instance, utilized in the field of biotechnology.
However, there are several difficulties with existing methods such as poor solubility in suitable solvents, particle agglomeration, long processing times and high losses that limit their applicability. The losses can be decreased with a continuous gas phase process such as spray drying, spray congealing or aerosol methods. In addition, gas phase methods enable efficient production of finely dispersed powders in well-controlled conditions with higher drug loads compared to conventional methods.
To overcome the flowability problem fine drug particles have been blended with coarse carrier particles. To improve the flowability further, the blend has been mixed with fine particle excipients, such as fine lactose, magnesium stearate, phospholipids and L-leucine function as lubricants between surfaces. Coating of the inhalable powders can also be carried in situ in particle production. For example, spray-freeze-dried proteins have been shown to result in low density particles with a rough surface. Amino acids when co-spray-dried with drugs provided surface with reduced adhesion properties. However, the coating around particles is often non-uniform and the scaling of the process is difficult in many cases. The ability to modify the surface of particles in situ in the gas phase simplifies the production dramatically and also reduces the cost of high quality particles.
Consequently a method to produce large quantities of aerosol particles containing an active agent and a surface modifying agent with well controlled surface properties so as to have superior flowability, stability, deagglomeration efficiency and/or dissolution properties would be beneficial to industry and commerce. The present invention provides a simple and efficient method which is able to produce particles with consistent and controlled properties, including particle size and size distribution, shape, crystallinity, polymorphic phase, surface roughness, composition and chemical purity. Such particles are particularly well suited for drug delivery by inhalation.
The method of this invention for the in-situ synthesis of surface modified particles can easily be used for the either nano- or micron-sized particles and for a wide variety of materials. It enables the tailoring of the surface of particles composed of a wide variety of materials. The surface modification can be varied by varying the supersaturation of the coating material during the process. The processing time is short and dry surface modified particles can be obtained directly after the particle synthesis.